The candidate, James Robinson Ph.D. proposes a comprehensive five year research and training program within the Huntsman Cancer Institute part of the University of Utah. Familial Adenomatous Polyposis (FAP) is an inherited syndrome characterized by the development of hundreds of pre- cancerous polyps in the large intestine, some of which progress to cancers. Prophylactic colectomy is usually performed as a preventative measure. FAP is caused by germline mutations in the Adenomatous Polyposis Coli (APC) gene. APC mutations are also found in sporadic colorectal adenomas and 85% of colon cancers carry APC mutations. Consequently, FAP is an excellent model for the study of colon cancer because each adenoma represents an early step in tumorigenesis. Until recently it was widely accepted that APC mutations were alone sufficient for nuclear accumulation of ?-Catenin in intestinal epithelial cells and the onset of intestinal polyposis, but preliminary data suggests that additional growth signals or mutations are required. The candidate's hypothesis is that aberrant stromal cell signaling following loss or haploinsufficiency of APC drives tumorigenesis in adjacent predisposed epithelial cells. This project will expand the understanding of how stromal APC loss contributes to the development of neoplastic intestinal epithelium. The candidate's long-term research goals are to facilitate the development of new measures to prevent colonic adenoma formation by understanding the earliest cellular perturbations that follow APC mutation. If he can demonstrate that growth of early adenomas is driven by stromal signaling and identify which components of this signaling are potential therapeutic targets, completion of this project may radically improve measures to prevent and treat FAP and sporadic colon cancer. An accompanying research training program under the direction of Dr David Jones is a core component of the mentored (K99) period of the award, providing the candidate with a strong foundation in basic science, cancer research and the biology of colorectal cancer. This carefully developed research and training program will lead to: 1) important advances in the study of colorectal cancer, 2) the development of mouse models in which to test novel therapeutic agents, 3) the generation of data that will provide the basis for a highly competitive submission for R01 funding at the conclusion of the independent award (R00) period; and 4) transition of the candidate into an independent researcher.